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dc.contributor.authorBosse, Tanja
dc.contributor.authorEhinger, Julia
dc.contributor.authorCzuchra, Aleksandra
dc.contributor.authorBenesch, Stefanie
dc.contributor.authorSteffen, Anika
dc.contributor.authorWu, Xunwei
dc.contributor.authorSchloen, Kathrin
dc.contributor.authorNiemann, Hartmut H
dc.contributor.authorScita, Giorgio
dc.contributor.authorStradal, Theresia E B
dc.contributor.authorBrakebusch, Cord
dc.contributor.authorRottner, Klemens
dc.date.accessioned2008-03-05T09:59:13Z
dc.date.available2008-03-05T09:59:13Z
dc.date.issued2007-10
dc.identifier.citationCdc42 and phosphoinositide 3-kinase drive Rac-mediated actin polymerization downstream of c-Met in distinct and common pathways. 2007, 27 (19):6615-28 Mol. Cell. Biol.en
dc.identifier.issn0270-7306
dc.identifier.pmid17682062
dc.identifier.doi10.1128/MCB.00367-07
dc.identifier.urihttp://hdl.handle.net/10033/19757
dc.description.abstractActivation of c-Met, the hepatocyte growth factor (HGF)/scatter factor receptor induces reorganization of the actin cytoskeleton, which drives epithelial cell scattering and motility and is exploited by pathogenic Listeria monocytogenes to invade nonepithelial cells. However, the precise contributions of distinct Rho-GTPases, the phosphatidylinositol 3-kinases, and actin assembly regulators to c-Met-mediated actin reorganization are still elusive. Here we report that HGF-induced membrane ruffling and Listeria invasion mediated by the bacterial c-Met ligand internalin B (InlB) were significantly impaired but not abrogated upon genetic removal of either Cdc42 or pharmacological inhibition of phosphoinositide 3-kinase (PI3-kinase). While loss of Cdc42 or PI3-kinase function correlated with reduced HGF- and InlB-triggered Rac activation, complete abolishment of actin reorganization and Rac activation required the simultaneous inactivation of both Cdc42 and PI3-kinase signaling. Moreover, Cdc42 activation was fully independent of PI3-kinase activity, whereas the latter partly depended on Cdc42. Finally, Cdc42 function did not require its interaction with the actin nucleation-promoting factor N-WASP. Instead, actin polymerization was driven by Arp2/3 complex activation through the WAVE complex downstream of Rac. Together, our data establish an intricate signaling network comprising as key molecules Cdc42 and PI3-kinase, which converge on Rac-mediated actin reorganization essential for Listeria invasion and membrane ruffling downstream of c-Met.
dc.language.isoenen
dc.subject.mesh1-Phosphatidylinositol 3-Kinaseen
dc.subject.meshActinsen
dc.subject.meshAnimalsen
dc.subject.meshBacterial Proteinsen
dc.subject.meshCell Surface Extensionsen
dc.subject.meshEnzyme Activationen
dc.subject.meshHumansen
dc.subject.meshListeria monocytogenesen
dc.subject.meshMembrane Proteinsen
dc.subject.meshMiceen
dc.subject.meshMice, Knockouten
dc.subject.meshProto-Oncogene Proteins c-meten
dc.subject.meshRecombinant Fusion Proteinsen
dc.subject.meshSignal Transductionen
dc.subject.meshWiskott-Aldrich Syndrome Protein Familyen
dc.subject.meshWiskott-Aldrich Syndrome Protein, Neuronalen
dc.subject.meshcdc42 GTP-Binding Proteinen
dc.subject.meshrac1 GTP-Binding Proteinen
dc.titleCdc42 and phosphoinositide 3-kinase drive Rac-mediated actin polymerization downstream of c-Met in distinct and common pathways.en
dc.typeArticleen
dc.contributor.departmentCytoskeleton Dynamics Group, Helmholtz Centre for Infection Research (HZI), Inhoffenstrasse 7, D-38124, Braunschweig, Germany.en
dc.identifier.journalMolecular and cellular biologyen
refterms.dateFOA2018-06-12T21:39:55Z
html.description.abstractActivation of c-Met, the hepatocyte growth factor (HGF)/scatter factor receptor induces reorganization of the actin cytoskeleton, which drives epithelial cell scattering and motility and is exploited by pathogenic Listeria monocytogenes to invade nonepithelial cells. However, the precise contributions of distinct Rho-GTPases, the phosphatidylinositol 3-kinases, and actin assembly regulators to c-Met-mediated actin reorganization are still elusive. Here we report that HGF-induced membrane ruffling and Listeria invasion mediated by the bacterial c-Met ligand internalin B (InlB) were significantly impaired but not abrogated upon genetic removal of either Cdc42 or pharmacological inhibition of phosphoinositide 3-kinase (PI3-kinase). While loss of Cdc42 or PI3-kinase function correlated with reduced HGF- and InlB-triggered Rac activation, complete abolishment of actin reorganization and Rac activation required the simultaneous inactivation of both Cdc42 and PI3-kinase signaling. Moreover, Cdc42 activation was fully independent of PI3-kinase activity, whereas the latter partly depended on Cdc42. Finally, Cdc42 function did not require its interaction with the actin nucleation-promoting factor N-WASP. Instead, actin polymerization was driven by Arp2/3 complex activation through the WAVE complex downstream of Rac. Together, our data establish an intricate signaling network comprising as key molecules Cdc42 and PI3-kinase, which converge on Rac-mediated actin reorganization essential for Listeria invasion and membrane ruffling downstream of c-Met.


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